The present invention relates to improvements in and/or relating to intra vaginal devices.
Our PCT/NZ97/00052 (published as WO 97/40776) discloses a variety of different forms of intra vaginal devices of a variable geometry type for retention within the intra vaginal cavity of an animal. Such devices hitherto have primarily involved the use of a silicone rubber composition which as a matrix has been impregnated with an active pharmaceutical agent (eg progesterone). In the variable geometry type devices typified by the CIDR(trademark) devices of this company the impregnated matrix has primarily been supported on a spine of a resilient material such as nylon, the resilience of which is utilised for the variable geometry retention characteristics notwithstanding that such spine is usually fully overlaid with the impregnated matrix.
Various polymers have been used to deliver pharmaceutical agents, one such class of polymers extensively utilised for the delivery of pharmaceutical agents are the polyesters. Examples of these polymers include poly lactic acid, poly glycolic acid, poly (xcex5-caprolactone) and various co-polymers of lactide, glycolide and xcex5-caprolactone.
Pharmaceutical products utilising these polymers are typically formulated as microspheres, microcapsules, films, rods or blocks. Retention within a body cavity has been achieved by a number of methods, eg: the addition of dense fillers, injection or surgical implantation into muscle or subcutaneous areas.
Various agents may be employed to enhance the absorption of agents across mucosal membranes and into the blood circulatory system. One such class of agents extensively utilised for the enhanced absorption of agents are the cyclodextrins. Examples of the cyclodextrins include xcex1-cyclodextrin, xcex2-cyclodextrin, xcex3-cyclodextrin and hydroxypropyl xcex2-cyclodextrin.
Devices utilising these absorption enhancing agents are typically formulated as microspheres, microcapsules, tablets or liquids.
It is an object of the present invention to provide intra vaginal devices having the prospect of allowing for a given device size or loading an enhanced systemic uptake of an active ingredient or at least provide the public with a useful choice.
The present invention preferably relates to a device designed to deliver progesterone over an extended period of time (2 to 20 days) upon insertion into the vagina of mammals, eg: cattle, sheep, horses, pigs, goats, buffalo or deer. The device is preferably retained within the vagina preferably by means of a flexible geometric arrangement of arms with respect to a body portion.
Accordingly in a first aspect the present invention consists in a device for insertion into the vagina of a mammal, said device consisting of a matrix (preferably mouldable, eg: a polymer) containing both a cyclodextrin and an intra vaginally effective active ingredient.
As used herein, the term xe2x80x9cintra vaginally effective active agentxe2x80x9d means any compound or composition or complex that by means of delivery into the vaginal cavity of a mammal can be absorbed systemically by the mammal therefrom so as to achieve or suppress some physiological effect. Examples include progesterone (eg: for oestrus synchronisation and other purposes), and oxytocin (eg: for milk let down).
As used herein, the term xe2x80x9ccyclodextrinxe2x80x9d includes any suitable cyclodextrin or mixtures thereof.
As used herein, the term xe2x80x9cpolymerxe2x80x9d in respect of carrying matrix of the cyclodextrin and intra vaginally effective active agent includes any suitable polymer and need not be restricted to the preferred polymers hereinafter discussed.
In a second aspect the invention consists in an intra vaginal device having at least for a target species of appropriate size a form insertable and retainable in the vaginal tract, said device at least in part having a moulded matrix which includes both a cyclodextrin and an intra vaginally effective active agent.
In still a further aspect the present invention consists in an intra vaginal device for insertion into the vagina of a target species mammal, said device being or having a moulded progesterone and cyclodextrin impregnated matrix of a biodegradable polymer selected from the group of poly esters and starch like polysaccharides, the cyclodextrin being of a kind and in such amount as will enhance release and/or adsorption.
Preferably said kind and amount of cyclodextrin will enhance adsorption.
Preferably said device has a variable geometry whereby after insertion in one geometry the device will assume another having a retention characteristic.
Preferably at least substantially all of the device is said impregnated matrix.
Preferably said polymer is poly (xcex5-caprolactone).
Alternatively said polymer is a starch-like polysaccharide.
Preferably the cyclodextrin is hydroxypropyl xcex2-cyclodextrin.
Preferably the cyclodextrin comprises from 5 to 70% w/w of the impregnated matrix.
Preferably the progesterone comprises from 5 to 70% w/w of the impregnated matrix.
Preferably the progesterone loading is from 0.1 to 3 gms.
Preferably the surface area of the impregnated matrix is from 15 to 200 cm2.
Preferably progesterone does not appear as a fine powder or crystal upon the surface of the device.
In yet another aspect the present invention consists in an intra vaginal device for insertion into the vagina of an animal, said device being intra vaginally insertable, intra vaginally retainable and withdrawable by virtue of its ability to change its geometry yet being formed at least almost exclusively from a cyclodextrin and progesterone impregnated moulded matrix of poly (xcex5-caprolactone), the loading of progesterone being from 0.1 to 3 gms and the surface area of the impregnated matrix being from 15 to 200 cm2.
In another aspect the invention is the use, for animal group oestrus synchrony purposes, of a device of the present invention.
In still another aspect the invention is a method of manufacturing of an intra vaginal device as defined which comprises or includes the steps of
including in the polymerisable precursor of said biodegradable polymer a distribution of both cyclodextrin and progesterone, and
thereafter moulding the device or the impregnated matrix of the device therefrom.
Preferably the whole device results from the moulding.
Preferably the cyclodextrin(s) comprise from from 5 to 70% w/w of the impregnated matrix.
Preferably the progesterone comprises from 5 to 70% w/w of the impregnated matrix.
Preferably said progesterone and cyclodextrin are pre-mixed prior to association with said polymerisable precursor.
In yet a further aspect the invention is a method of achieving in an animal (or in each animal of a group of animals) a blood serum level of progesterone of greater than 2 ng/ml for a period of at least 5 days, said method comprising inserting and retaining in the or each animal for at least the 5 day period a device of the present invention.
Preferably said device has a loading of from 0.1 to 3 gms of progesterone.
Preferably the animal(s) is or are of the cattle, sheep, goats or deer species.
Preferably said device has an impregnated matrix surface of from 15 to 200 cm2.
The invention is also an intra vaginal device of the present invention made by a method of the present invention.
In another aspect the invention is an intra vaginal device substantially as herein described with reference to any one or more of the accompanying drawings.
Preferably all polymer(s) of the said mass (if all, as is preferred, is to be moulded) can be moulded without use of conditions prejudicial to progesterone and any cyclodextrin (or for that matter, any other absorption enhancing agent) present.
The addition of particulate material such as progesterone to silicone in amounts greater than 20% w/w has been found to be detrimental to the structural integrity of the intra vaginal inserts. Silicone based intra vaginal inserts must include a spine of a material such as Nylon or stainless steel, over which the silicone is moulded, to maintain a configuration conducive to vaginal retention. The addition of large amounts of particulate material has been found to reduce the strength of the silicone such that the spine may rupture and protrude through the other silicone laminate.
The invention also consists in a method of achieving with an animal (or group of animals) a blood serum level of greater than 2 ng/ml for a period of at least 5 days of progesterone, said method comprising inserting and retaining in the vagina of each animal for at least the 5 day period a device of any of the kinds of the present invention.
Preferably said device has a loading of from 0.1 to 4 gms of progesterone for the target animals such as cattle, sheep, goats, deer, etc.
Preferably said device has an impregnated matrix surface of from 15 to 200 cm2.
The present invention also consists in a method of manufacture of an intra vaginal device which results in a device in accordance with the present invention, and/or vice versa.